Antagonists of luteinizing hormone releasing hormone bind to rat mast cells and induce histamine release

Abstract

It was reported previously that administration of certain synthetic antagonists of LHRH to rats produced allergy-like symptoms that were attributed to their histamine releasing action. In the present study the interaction of LHRH analogs with rat peritoneal mast cells was investigated in vitro. Potent antagonists of LHRH showed strong in vitro histamine releasing activity from rat peritoneal mast cells. Membrane preparations of rat pituitary glands showed specific binding of radioiodinated LHRH antagonist as well as LHRH agonist. However, rat peritoneal mast cells and membrane preparations from those cells bound antagonist but not the agonist. Furthermore, the LHRH antagonist did not bind to membranes prepared from tissues such as prostate, liver, kidney, and brain. Competitive displacement curves of the [125I]-antagonist with different LHRH analogs showed that the ability of the analogs to compete for binding sites on mast cells was related to their histamine releasing activity. We conclude that histamine release from rat mast cells induced by LHRH analogs is mediated by specific binding of the active peptides to cell membranes. Furthermore, using rat mast cells, the binding assay in conjunction with histamine releasing assay may be utilized to predict the in vivo histamine releasing potential of new LHRH peptides which are of clinical importance.

Mast cells with gonadotropin-releasing hormone-like immunoreactivity in the brain of doves.

“…Mast cells can contain at least 20 mediators (41) including interleukins, granulocyte/macrophage colonystimulating factor (42), and a variety of proteoglycans, proteases, and neuropeptides (3,39). Of particular interest for this and related studies (1, 2) is the clinical observation that histamine secretion from mast cells and cutaneous anaphylaxis can be induced with GnRH (43) and GnRH agonists and antagonists (43)(44)(45). Mast cells respond not only to GnRH and its analogues but also to gonadal steroids.…”

Starving the Addiction: New Opportunities for Durable Suppression of AR Signaling in Prostate Cancer

“…Like GnRH agonists, these agents prevent testicular androgen synthesis, but fail to induce the transient testosterone flare associated with GnRH agonists (38, 39). Administration or use of first generation GnRH antagonists such as abarelix was limited by untoward side effects (27, 40), but recent modifications to the structure of the product resulted in reduced immunostimulatory activity and safer administration (41). One such second generation product, degarelix, can suppress circulating androgen levels without inducing testosterone flares or allergic reactions (42, 43).…”

Mast cells in the rat brain synthesize gonadotropin‐releasing hormone

“…The action of GnRH-I as a mast cell activating molecule was discovered when GnRH-I and its analogues were used in the treatment of precocious puberty. Such treatment induced histamine secretion from mast cells, leading to cutaneous anaphylaxis (Sundaram et al, 1988;Rivier et al, 1986;Phillips et al, 1988). For this reason, novel GnRH analogues for the treatment of this disorder have been designed to circumvent these adverse clinical effects (Jiang et al, 2001).…”